LBL team discovers gene linked with heart disease

January 10, 1992

By Lynn Yarris,

LBL scientists have discovered a gene that predisposes individuals to atherosclerosis, the leading cause of heart disease in this country. Designated ATHS (for atherosclerosis susceptibility), the gene has been located on chromosome 19.

Ronald Krauss, physician and senior scientist with LBL's Research Medicine and Radiation Biophysics Division, discovered the gene in collaboration with Patsy Nishina, John Johnson, and Jurgen Naggert, all with the Children's Hospital Oakland Research Institute. The study was reported in the Jan. 5 issue of the Proceedings of the National Academy of Science.

Atherosclerosis is the clogging of arteries through the buildup of fatty deposits primarily by low density lipoprotein (LDL) or "bad cholesterol." In 1986, Krauss headed a hereditary study that demonstrated the existence of an atherogenic lipoprotein phenotype, a genetic trait which is shared by up to 30 percent of the population. Statistical evidence linked this phenotype to a single gene.

"Inheritability can be deceptive and statistical indicators are a black box until you find the evidence for a gene," Krauss says. "We now have conclusive proof that the gene exists, and we know where it is."

Krauss calls ATHS a classical susceptibility gene in that, "It doesn't cause atherosclerosis by itself, but works with other factors, such as diet and possibly other genes, to put those individuals who carry it at greater risk."

The atherogenic lipoprotein phenotype is characterized by an imbalance in the blood of bad and good cholesterol, resulting in a three-fold increase in the rate of heart problems. Studies have shown that this trait generally does not show up in men until after the age of 20, or in women until after menopause. To find the gene responsible for the atherogenic lipoprotein phenotype, the LBL-Children's Hospital collaborators used what is called a "candidate gene" approach to linkage analysis.

In genetics, when groups of traits are inherited together, they are said to be "linked." Linkage is a reflection of physical proximity -- the stronger the link, the greater the likelihood that the genes are located near one another on the same chromosome. Krauss and his collaborators tested ATHS for possible linkage to a number of known genes that are associated with LDLs and with diabetes since the atherogenic lipoprotein phenotype is also predisposed to that disease.

"We found strong linkage to both the LDL and the insulin receptor genes on the short arm of chromosome 19," says Krauss. "It appears quite likely that our gene is either a variation of the LDL receptor gene or else very close to it."

The LDL receptor gene which was first identified in the 1970s has been extensively studied for its role in metabolism, but has not previously been linked to the atherogenic lipoprotein phenotype.

Says Krauss, "Its role in atherosclerosis may have been missed because identifying the phenotype is so difficult."

Although the findings of Krauss and his group will require confirmation by other researchers, preparations are already underway to determine whether ATHS is indeed a new gene or a variation of the LDL receptor gene. Regions of DNA on chromosome 19 adjacent to the receptor gene will tested for even stronger linkage to ATHS. At the same time, LDL receptor genes from families with members that carry the atherogenic lipoprotein phenotype will be cloned and examined for variations between those from affected and unaffected relatives.

Once the most common DNA sequence of ATHS has been determined, Krauss says, scientists can then work to design a test that will be able to screen for the gene and identify those individuals who are at a higher risk of heart disease.

This research was supported by the National Dairy Promotion and Research Board, and by the National Institutes of Health.